TGF-β1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, due to excess amyloid-β peptide (Aβ). TGF-β1 and β-catenin signaling pathways have been separately implicated in modulating Aβ-neurotoxicity. However, the underlying mechanisms remain unclear. Here, we report that TGF-β1 and nuclear Smad7 and β-catenin levels were markedly upregulated in cortical brain regions of the TgCRND8 mice, a mouse model of familial Alzheimer's disease. Coimmunoprecipitation of cortical brain tissue lysates revealed an interaction between Smad7 and β-catenin. This interaction which was significantly enhanced in the TgCRND8 mice was also associated with an increase in TCF/LEF DNA-shift binding activity. TCF/LEF reporter gene activity was significantly increased in mouse primary cortical neuronal cultures (MCN) from the TgCRND8 mice, compared to controls. Interestingly, exposure of MCN to Aβ1-42 led to an increase in TGF-β1 and nuclear levels of both β-catenin and Smad7. Furthermore, addition of TGF-β1 to the MCN caused an increase in apoptosis and Smad7 levels. When Smad7 or β-catenin levels were reduced by siRNA, TGF-β1-induced apoptosis was suppressed, indicating that both Smad7 and β-catenin are required for TGF-β1-induced neurotoxicity. Since Aβ1-42-induced TGF-β1, we suggest that TGF-β1 may amplify Aβ1-42-mediated neurodegeneration in AD via Smad7 and β-catenin interaction and nuclear localization. © 2007 Elsevier Ireland Ltd. All rights reserved.